Menopause Int 2008;14:149-154
doi:10.1258/mi.2008.008018
© 2008 British Menopause Society
Obesity and arthritis
Malgorzata Magliano
Department of Rheumatology, Stoke Mandeville Hospital, Aylesbury, UK
Correspondence: Malgorzata Magliano, Consultant Rheumatologist, Department of Rheumatology, Stoke Mandeville Hospital, Mandeville Road, Aylesbury HP21 8AL, UK. Email: malgorzata.magliano{at}buckshosp.nhs.uk
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Abstract
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Obesity affects over 20% of the UK's adult population and its
prevalence is rising. Obesity can lead to a variety of musculoskeletal
problems and is independently associated with locomotor disability
and joint pain. Obesity increases the risk of radiographic knee
osteoarthritis (OA), but has a lesser effect on disease progression.
The association with hip and hand OA is weaker, but implies
that excess adipose tissue produces humoral factors, altering
articular cartilage metabolism. It has been postulated that
the leptin system could be a link between metabolic abnormalities
in obesity and increased risk of OA. Although obesity was initially
thought to increase the risk of rheumatoid arthritis (RA), further
studies showed, that heavier patients with RA have less radiological
disease progression and possibly better survival. On the other
hand, obesity is strongly associated with hypeuricaemia and
gouty arthritis. High body weight correlates independently with
metabolic syndrome and may contribute to increased cardiovascular
morbidity in patients with gout. Weight reduction should be
an important part of treatment for OA and gout. Because obesity
at a young age correlates with the development of OA and gout
in later life, preventive public health strategies aimed at
lowering the incidence of obesity are of most importance.
Key Words: Obesity • overweight • osteoarthritis • rheumatoid arthritis • gout • leptin
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Introduction
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Obesity has become a global problem leading to excess morbidity
and mortality. According to the latest World Health Organization
projections, more than 1.6 billion adults (age 15 + years) are
overweight; and at least 400 million are obese worldwide (Box
1).
1 UK data from the 2003 Health Survey for England reported that
33% of women and 43% of men over the age of 16 were overweight,
whereas 23% and 22%, respectively, were obese. The Department
of Health forecasts, that by the year 2010, a one-third of the
UK's adult population will be obese.
2 Disease burden from excess
weight is significant, including cardiovascular disease, diabetes,
dyslipidaemia, sleep apnoea and certain cancers.
3 Increased
weight leads to a number of musculoskeletal problems and these
are listed in Box
2.
| Box 1 Body mass index World Health Organization definitions use body mass index (BMI), defined as the weight in kilograms divided by the square of the height in metres:
- Overweight BMI >25 kg/m2
- Obese BMI>30 kg/m2
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Box 2 Musculoskeletal problems linked with obesity- Osteoarthritis
- Back pain
- Gout
- Plantar fascitis
- Chronic musculoskeletal pain
- Inflammatory arthritis
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This review summarizes epidemiological data on obesity and arthritis with particular emphasis on osteoarthritis (OA), rheumatoid arthritis (RA) and gout. It also discusses new insights into the potential role of adipose tissue in arthritis pathogenesis and its outcome.
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Methods
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An electronic search of Medline (1966–February 2008) via
Pubmed, Embase (1980–February 2008) and Cochrane Library
for papers published in English language was carried out. The
following keywords were used: (obesity or overweight) and (arthritis
or OA or RA or gout) and (epidemiology or case-control study
or cross-sectional study or cohort study or controlled trial).
The following criteria were used to select the studies: (1) the article was written in English; (2) the article was available in full-text format; (3) the study was of a cohort, case-control or cross-sectional design; (4) the publication was a meta-analysis or systematic review; (5) the study was a randomized controlled trial (RCT).
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Obesity and arthritis: is there an association?
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Joint pain is a common complaint particularly in older people.
A Scottish survey of 858 people aged 58 demonstrated a high
prevalence of pain affecting the knees, hips, hands, neck and
back.
4 The frequency of hip and knee pain was twice as high
in obese respondents. The Australian population survey of 7500
people reported that twice as many overweight responders were
given a diagnosis of arthritis, compared with people with normal
body mass index (BMI), regardless of their age and socioeconomic
status.
5
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Effect of obesity on incidence of OA
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It is well accepted that obesity constitutes a risk factor for
OA. OA is the commonest form of arthritis, affecting up to 8.5
million people in the UK and is becoming one of the main causes
of disability in the ageing population. OA is a clinical syndrome
of joint pain and functional limitation that results from the
loss of articular cartilage, the remodelling of subchondral
bone and synovial hypertrophy. It most commonly affects knees,
hips and hands.
In clinical practice the diagnosis of OA is based on the presence of joint pain and radiological changes, such as joint space narrowing and osteophyte formation, although it is well recognized that the two do not often correlate. This leads to certain difficulties in the interpretation of epidemiological studies. For example, studies selecting patients with OA who attend secondary care are difficult to compare with population-based cohort studies when the diagnosis is based on radiological features only regardless of patient's symptoms. Moreover, radiographs are taken in different positions and different scoring systems are used. There are, however, a significant number of well-designed studies showing positive association between obesity and OA. This has been most consistently demonstrated for knee OA.
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Obesity and knee OA
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Large cross-sectional population studies reported high BMI to
be an important independent risk factor for radiographic knee
OA.
6–8 Moreover, a linear trend in the relative risk of
knee OA with increasing BMI was demonstrated.
6,8,9 A population
survey of over 5000 people in the USA found that for every five
unit increase in BMI, the risk of radiographic change consistent
with knee OA was doubled.
6 Case-control studies of patients
with severe primary OA, selected from waiting lists for joint
replacement therapy, found those patients to be significantly
heavier than age and gender-matched controls.
8,10,11 The Australian
population-based cohort study of 224 healthy postmenopausal
women demonstrated a gradual increase in body weight (mean of
4 kg) over an 11-year follow-up period. This showed only a modest
association between body weight and radiological OA.
12 Stronger
association between BMI and knee OA was demonstrated in the
UK four-year prospective study of 830 middle-aged women. The
risk of developing osteophytes on knee radiographs was twice
as high in women in the top BMI tertile (BMI >26.4) compared
with women with BMI <23.4.
13 The association between high
BMI and knee OA appears to be stronger in women compared with
men, suggesting a role of estrogens in disease pathogenesis.
7,8,10 Having established an association between obesity and knee OA,
the question of causality arises. Does obesity precede arthritis
or is arthritis a consequence of limited mobility resulting
from joint damage and malfunction?
A number of longitudinal studies addressed this issue. A 36-year follow-up of 1420 participants for the Framingham Heart Study demonstrated that being heavier at the beginning of the study (mean age of 37) and at final follow-up (mean age of 73) were both associated with an increased risk of developing knee OA. This risk showed stepwise increase in women with each quintile increase in weight, whereas in men, it was only demonstrated for the heaviest group.7 Others endorsed the link between being overweight at younger age and development of knee OA later in life.14 Further data from the Framingham Study demonstrated that women who gained weight during the study period had increased incidence of OA with odds ratio 1.6 (95% confidence interval [CI] 1.2–2.3) for each 10 lb of weight.15 Prospective studies confirmed that obesity contributes to radiological disease progression in patients with knee OA.9,16 It appears, however, that the effect of high BMI on disease incidence is stronger than its effect on disease progression.9 This may be because other mechanical factors, such as joint alignment, play a greater role in disease evolution. BMI positively correlates with more severe joint space narrowing in the medial tibiofemoral compartment in patients with varus, but not with neutral or valgus knee alignment.17 Others reported links between increasing BMI and radiographic disease progression in patients with moderate malalignment, but not in those with neutral alignment or severe malalignment.18
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Obesity and hip OA
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Mechanical load and the effect of obesity on OA development
is different in the hip joint. No link between obesity or body
fat distribution and hip OA was found in a large cross-sectional
USA study of 2358 people over the age of 55.
19 A Swedish case-control
study of 259 men who underwent hip arthroplasty for primary
OA showed a positive association between severe hip OA and high
BMI.
20 A number of large cohort studies confirmed this correlation.
21,22 Interestingly, obesity at younger age was associated with higher
risk of hip OA than obesity in later life.
21 Prospective data
from the USA Nurses' Health study showed that high BMI at the
age of 18 increases the risk of total hip replacement in older
age with relative risk as high as 7.4 (95% CI 3.6–15)
when comparing the highest and lowest BMI categories.
23 In conclusion,
association between obesity and the incidence of hip OA is moderate;
nonetheless, risk appears to be higher for those who are overweight
at a younger age.
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Obesity and hand OA
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There is increasing evidence of a link between obesity and hand
OA. Radiographic changes consistent with OA are found in 40–50%
of people over the age of 50 and the incidence rises with increasing
age. A number of cohort studies have demonstrated that being
overweight is an additional independent risk factor for hand
OA.
24–26 Moreover, it is the baseline weight at younger
age that is predictive of hand OA rather than net weight gain
over the follow-up period.
24 Others have either shown that only
overweight male patients have an increased risk of hand OA or
have not demonstrated an association.
27–29
The association between obesity and OA in non-weight-bearing joints is difficult to explain. It has been postulated that metabolic changes associated with obesity, such as impaired glucose tolerance, hyperuricaemia and altered lipid profile, may have detrimental effects on articular cartilage metabolism. Studies examining the effect of these factors as well as studies of body fat distribution did not produce any consistent findings.26,30 Given that both OA and obesity have strong genetic predisposition, it was postulated that they share a common inheritance pathway. A twin pair cross-sectional study of healthy women showed a strong association between the increasing BMI and frequency of radiological knee OA, yet no evidence for a common genetic pathway.31
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Obesity and joint pain and disability
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Epidemiological studies of risk factors for the development
of OA use radiological criteria to make a diagnosis and monitor
progress. As mentioned before, the correlation between X-ray
appearances and the level of pain and disability is, however,
poor. A prospective study of 2895 people examined the effects
of pain and radiographic hip and knee OA on the levels of locomotor
disability (walking, climbing stairs, getting in and out of
bed, bending, rising from a chair).
32 Only 16% of men and 33.2%
of women with radiological hip OA had hip pain. Similarly, 25.4%
of men and 34.2% of women with radiological knee OA complained
of knee pain. Yet pain is a major predictor of impaired physical
function and a common indication for joint arthroplasty. A UK
population survey of over 50s found that the risk of developing
severe knee pain was 2.7 times higher among obese participants
compared with those with BMI < 25, after adjustment for age,
gender, whole body pain, psychological distress and history
of knee injury.
33 The association between increasing BMI and
intensity of knee pain in elderly women has been demonstrated
by others.
34 Women with radiological hip OA and pain were heavier
compared with asymptomatic women.
35
Obesity has been linked with physical disability.32,36 Impaired locomotor function was reported in 60% of 745 people with knee OA followed-up for an18-month period.36 Being overweight or obese was associated with poor outcome with adjusted risk ratio of 1.50 (95% CI 1.04–2.15) and 1.64 (95% CI 1.14–2.38), respectively. Furthermore, obese females were found to have an increased perception of physical disability in performing tasks of daily living compared with women with normal weight.37
Obesity is a significant independent risk factor for OA of the knee joint and contributes to the development of hip and hand OA. Its effect on disease progression is probably small. High BMI is also linked to the incidence of joint pain and locomotor disability.
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Obesity and metabolic syndrome/inflammation
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Involvement of the non-weight-bearing joints in OA suggests
the role of humoral/metabolic factors in disease pathogenesis.
The discovery of leptin, a small polypeptide produced in white
adipose tissue, which is involved in the regulation of energy
storage and expenditure, increased our understanding of the
interaction between fatty tissue and the immune system (Box
3).
Leptin levels correlate with adipose tissue mass and are high
in obese individuals. In patients with OA, leptin was detected
in synovial fluid and its levels correlated with BMI.
38 Moreover,
leptin is expressed on human chondrocytes and has a stimulatory
effect on proteoglycan synthesis, which may be important in
bone formation observed in OA.
Box 3 Interactions of leptin with immune system- Activation of monocytes/macrophages leading to release of tumour necrosis factor (TNF)-
 and Il-6
- Increases leptin levels following inflammatory stimuli, such as TNF-, Interleukin-2 (IL-2) and lipopolysaccharide
- Promotes differentiation of Th-naïve T-cells into Th1 phenotype
- Stimulation of chondrocyte synthetic activity
- Stimulation of endothelial cells and angiogenesis
- Stimulation of transforming-growth factor production and possibly a role in osteophyte formation
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Obesity and inflammatory arthritis
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Adipose tissue is also an important source of interleukin-6
(Il-6), and since Il-6 stimulates the hepatic production of
C-reactive protein (CRP), positive correlation has been shown
between CRP levels and abdominal obesity. It has, therefore,
been suggested that obesity may be a risk factor for inflammatory
arthritis.
Case-control studies suggested a higher risk of RA in obese women;39,40 however, this finding was not confirmed by larger cohort studies.41,42 Does obesity influence outcome in patients with inflammatory arthritis?
Two prospective studies compared the progression of radiological joint damage in patients with normal body weight and overweight patients.43,44 After correcting for other disease-relevant variables, high BMI at the beginning of disease was associated with better radiological outcome over a 2–3-year follow-up period. In contrast, patients with normal body weight and seropositive disease were three times as likely to develop radiological joint damage.44 Weight loss is not uncommon in patients with severe rheumatoid disease, so does BMI has an effect on survival in patients with RA?
An American cohort study of 779 patients with RA found a significantly lower mortality in heavier patients after adjustment for age, gender, disease duration, smoking and the use of methotrexate.45 Lean patients had more co-morbidities, which partially explains the worse survival in this group. The protective effect of higher BMI was also reduced after adjusting for erythrocyte sedimentation rate (ESR) levels, showing the highest survival in overweight/obese patients with low ESR. Interestingly, high BMI is linked to an increased survival in patients with severe congestive cardiac failure and patients on chronic dialysis.46 This reversed survival advantage has been linked to malnutrition–inflammation complex syndrome, in which cachexia and muscle wasting are linked to circulating high levels of proinflammatory cytokines, mainly tumour necrosis factor (TNF-), leading to a state parallel to severe RA.
The discovery of the leptin system prompted further research, examining its role in the pathogenesis of inflammatory arthritis. Leptin belongs to the type I cytokine family and its expression is regulated by proinflammatory mediators.47 Murine models of autoimmune diseases such as antigen-induced arthritis and leptin-deficient mouse (ob/ob) showed reduced disease susceptibility.47 The precise role of leptin in RA remains unclear. Levels of leptin have been shown to be higher in RA patients compared with healthy controls in some studies. Although one study demonstrated the inverse correlation of leptin with CRP and Il-6, this finding was not confirmed by others.48 Similarly, no differences in synovial fluid leptin levels were found between patients with RA and healthy controls.49 Treatment with anti-TNF- monoclonal antibody does not reduce leptin levels despite an improvement in disease activity score and normalization of Il-6 levels, suggesting that leptin does not play a central role in the inflammatory process in RA.50
It is, therefore, likely that more rapid radiological progression in lean patients with RA simply reflects more severe disease and higher circulating levels of proinflammatory cytokines, such as TNF-. It is also possible that adipocytes, which are present in the synovial tissue of overweight patients with RA, produce local anti-inflammatory factors such as adiponectin and have a protective effect on joint cartilage. Further research is required in this area.
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Obesity and gouty arthritis
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In contrast to OA and RA, gouty arthritis is the most common
inflammatory arthritis affecting adult men. Gouty arthritis
is strongly associated with hyperuricaemia resulting from excess
purine intake and/or renal under secretion of uric acid. The
correlation between uric acid levels and body mass has been
well described.
51 A longitudinal study of 1337 medical students
found that BMI at the age of 35 was associated with an increased
risk of gout in a positive linear fashion, after adjustment
for age and the presence of hypertension.
51 Another cohort study
of 47,150 men with no previous history of gout confirmed graded
association between BMI and the risk of gouty arthritis. For
obese men, the relative risk of gout was almost three times
as high as for men with a BMI of 21–22.9. Furthermore,
weight gain from the age of 21 years increased the risk of gout,
whereas weight loss >10 Ib reduced it by almost 40%.
52 Central
obesity, expressed as increased waist-to-hip ratio, was shown
to increase the risk of incident gout by two-to-three-fold,
independently of BMI.
53 In Korean patients with gout, BMI was
associated with metabolic syndrome (high waist-to-hip ratio,
hyperlipidaemia, hypertension and diabetes).
54 Others showed
that in patients with hyperuricaemia, obesity constitutes an
independent cardiovascular risk factor.
55 The mechanism of this
effect, however, is not understood and requires further investigation.
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Conclusion
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There is a well-demonstrated link between obesity and musculoskeletal
problems. Obesity is a risk factor for incidence OA, particularly
in the knee joint, implying a detrimental effect of excess loading
on the joint structures. Weaker association between high BMI
and OA of the hip joint and hand raises the question of whether
adipose tissue has metabolic/humoral effects on articular cartilage,
and the role of adipokines have been implied in OA pathogenesis.
Patients with OA present with pain and functional impairment,
which correlates poorly with radiographic changes. Obesity seems
to be an independent risk factor for joint pain and locomotor
disability. A meta-analysis of RCTs of weight loss on the symptoms
associated with knee OA concluded that weight reduction of at
least 5% of the original weight within a 20-week period consistently
predicted a reduction in physical disability but not pain.
56 The most effective intervention was a combination of modest
weight loss (of 5%) and moderate exercise (three hourly sessions
weekly).
57 On the other hand, data from the Framingham cohort
study demonstrated that weight loss had a significant effect
on lowering the risk of symptomatic knee OA estimated as 50%
reduction per two units of BMI over 10 years.
58 Weight loss
and exercise should therefore be recommended at least to patients
with symptomatic knee OA.
Although obesity was initially thought to increase the risk of RA, further studies suggest that heavier patients have less radiological disease progression and possibly better survival. This may represent the effect of cytokine-induced cachexia, characterizing patients with more severe RA, but the protective effects of leptin on articular cartilage have been postulated and require further investigation.
Obesity is associated with hyperuricaemia and gout, and may contribute to increased cardiovascular risk in these patients. Weight reduction has been shown to reduce serum uric acid levels and the frequency of gouty attacks and should constitute an important part of gout management.
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Summary of the main findings
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- Obesity significantly increases the risk of knee OA.
- It has a positive but lesser effect on the risk of hip and hand OA.
- Obesity is an independent risk factor for locomotor disability and pain.
- Obesity has a significant association with hyperuricaemia and gout, as well as metabolic syndrome.
- In RA, obesity is linked to lesser radiological disease progression.
- The role of adipokines in the pathogenesis of OA needs further research.
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Competing interests
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None declared.
Accepted: May 2, 2008.
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